Anesth Analg 2000;91:1066-1072
© 2000 International Anesthesia Research Society
CARDIOVASCULAR ANESTHESIA
Neuronal and Astroglial Injuries in Patients Undergoing Coronary Artery Bypass Grafting and Aortic Arch Replacement During Hypothermic Cardiopulmonary Bypass
Dmitry N. Derkach, MD,
Hirotsugu Okamoto, MD, PhD, and
Shosuke Takahashi, MD, PhD
Department of Anesthesiology and Critical Care Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan
Address correspondence to Hirotsugu Okamoto, MD, PhD, Department of Anesthesiology, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa, 2248-8555, Japan. Address e-mail to okasuke{at}med.kitasato-u.ac.jp
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Abstract
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More than 50% of patients suffer neuropsychologic impairment after cardiac surgery. We measured neuron-specific enolase (NSE) and S-100 protein (S-100) in patients’ serum as putative markers of neuronal and astroglial cell injury, respectively. Group I (n = 13) underwent coronary artery bypass grafting (CABG) with mild hypothermic cardiopulmonary bypass (CPB); Group II (n = 6) underwent aortic arch replacement with deep hypothermic CPB; Group III (n = 8) underwent CABG under normothermia without CPB. During and after the operation, serum levels of NSE and S-100 were significantly increased only in Groups I and II (during CPB), NSE still being increased 12 h after surgery in Group II. This suggests that neuronal and astroglial cell injuries are more likely in patients undergoing CABG with mild hypothermic CPB or aortic arch replacement with deep hypothermic CPB than in those undergoing CABG under normothermia without CPB. However, these increases of NSE and S-100 failed to reflect clinical brain damage. Rather, an electroencephalogram, was only capable of detecting neurologic complications after surgery.
Implications: Neuronal and astroglial cell injuries are likely to occur during coronary artery bypass grafting with mild hypothermic cardiopulmonary bypass (CPB) or aortic arch replacement with deep hypothermic CPB. Conversely, patients undergoing coronary artery bypass grafting without CPB under normothermic conditions may be less likely to suffer brain cell injury.
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Introduction
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Postoperative neurological deficits occur in 0.8%–5.2% of patients undergoing cardiac surgery, whereas neuropsychologic disorders occur in 26%–79% of such patients (1). Cerebral ischemia resulting from inadequate cerebral perfusion or microemboli are thought to be possible causes of these neurological and neuropsychological impairments (2). Both physiological and biochemical monitors and markers, such as electroencephalogram (EEG), near infrared spectroscopy (NIRS), transcranial Doppler (TCD), jugular venous oxygen saturation (SjO2), and jugular venous lactate concentration (Sj lactate), are considered important for early detection and treatment of cerebral ischemic events (3). Although these monitors and markers can detect global cerebral ischemia or severe focal ischemia resulting in neurological deficits, mild cerebral ischemia leading to subclinical neurological dysfunction or subtle changes in higher cognitive functions cannot easily be detected. Neuron-specific enolase (NSE) and S-100 protein (S-100) are released after injury from the cytosol of neurons and astroglial cells, respectively (4,5) and can be used as biochemical markers for the detection of minor brain injury during cardiac surgery (6). Both NSE and S-100 are increased in the serum during hypothermic cardiopulmonary bypass (CPB), and the increase in these markers is related to cerebral complications after surgery (7,8). However, there has been no study in which NSE, S-100, and other monitors and markers have been monitored simultaneously throughout the different types of cardiac surgery with or without CPB.
The purposes of the present study were to further characterize the time course of the changes of NSE and S-100 during cardiac surgery and to compare the changes of NSE and S-100 during three types of cardiac surgery: namely, coronary artery bypass grafting (CABG) with mild hypothermic CPB, CABG without CPB, and aortic arch replacement (AAR) with deep hypothermic CPB. In addition, we simultaneously recorded and measured currently available physiological and biochemical monitors and markers (EEG, NIRS, TCD, SjO2, and Sj lactate).
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Methods
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This research was performed at the Kyushu University Hospital with the approval of the institutional ethics committee. Patients for this study were chosen randomly from patients scheduled for cardiac surgery in Kyushu University Hospital. Informed consent was obtained from each patient before the operation. Patients with a history of head trauma, seizures, or brain tumors were excluded. Twenty-seven patients were divided into three groups according to the type of surgery: roup I had 13 patients undergoing CABG with mild hypothermic CPB, Group II had 6 patients undergoing AAR with deep hypothermic CPB and retrograde cerebral perfusion, and Group III had 8 patients undergoing CABG without CPB under normothermic conditions (beating heart surgery). Four other patients were excluded from the research protocol because we failed to localize the catheter tip in the bulb of the internal jugular vein (2 patients) or because severe hemolysis occurred (2 patients) during CPB.
All patients were premedicated with nitrazepam 5–7 mg 2 h before surgery. Anesthesia was induced with fentanyl (0.01–0.02 mg/kg) and diazepam (0.2 mg/kg). After endotracheal intubation aided by pancuronium (0.1 mg/kg), fentanyl (0.25–0.5 mg/h) and diazepam (1.0 mg/h) were used for the maintenance of anesthesia. The extracorporeal circuit consisted of a membrane oxygenator (D 903 AvantTM Dieco, Mirandola, Italy), silicon tubes, a reservoir, and an arterial filter. Acetated Ringer’s solution supplemented with 60 mEq of bicarbonate, 40 g of mannitol, and 200 mL of 25% albumin per liter was used to prime the circuit. Hydrocortisone 50 mg/kg, heparin 3 mg/kg, and tranexamic acid 50 mg/kg were given before aortic cannulation. CPB was performed by using nonpulsatile perfusion during mild hypothermia in Group I (arterial blood temperature from oxygenator 28°C, nadir PA blood temperatures (29°–32°C) and during deep hypothermia in Group II (arterial blood from oxygenator 16°C, nadir PA blood temperature 16°–20°C). The pumpflow rate and the retrograde cerebral perfusion flow rate were maintained at 2.2–2.5 L · min-1 · m-2 and 0.3–0.5 L · min-1 · m-2 respectively. Acid-base management during CPB was achieved by using an alpha-stat strategy, and mean arterial blood pressure was maintained at 50–80 mm Hg. In Group III, aortic and venous cannulations for CPB were performed as in Groups I and II, but the CABG was performed without CPB under normothermic conditions.
Monitors included TCD (Mediasonics, Fremont, CA), NIRS (INVOS 3100A Cerebral OximeterTM; Somanetics, Troy, MI) and EEG (Nihonkohden, Tokyo, Japan). SjO2) (Oxymetrix-3 SO2/CO ComputerTM; Abbot Critical Care Systems, Mountain View, CA) was measured by way of a catheter (5.5F) positioned with the aid of radiographic examination in the bulb of the internal jugular vein. SjO2 measurements were calibrated by gas analysis of samples taken from the distal port. Monitoring of TCD was unilateral (right side). After intubation, TCD detector was adjusted in the projection of the middle cerebral artery and fixed in the position with highest signal amplitude. NIRS monitoring was bilateral with sensors fixed on both right and left sides of forehead.
Standard preoperative and postoperative neuro-assessments were performed by neurologists for all patients. The standard neuro-assessment consists of testing sensory and motor nerve function, cranial nerve function, deep tendon reflexes of extremities, pathetic reflexes, and mental (neuropsychological) status by conducting brief calculations and conversation. Computed tomography examination (CT) was available for patients with perioperative clinical evidence of neurological deficit or seizures.
Blood samples for NSE, S-100, and lactate analysis were drawn from the distal port of the SjO2 catheter. Jugular venous and arterial lactate concentrations were determined by using a lactate and glucose analyzer (2300TM; YSI, Yellow Springs, OH). Blood 5 mL, for NSE and S-100 analysis was centrifuged for 10 min, and serum was frozen until assayed. For NSE content determination, the sandwiched immunoradiometric assay system described by Johnsson et al. (7) was used (NSE RIA kitTM; Eiken, Tokyo, Japan). Standard NSE and samples were incubated for 90 min with anti-NSE antibody beads and 125I-labeled anti-NSE antibody. After washing out excess 125I-labeled materials, the amount of radioactive antibody was measured by using a gamma counter. S-100 was analyzed by using the enzyme immunoassay originally described by Usui et al. (9). After immobilizing anti-S-100 antibody using a microplate, standard S-100 and samples were incubated overnight with peroxidase-labeled anti-S-100 antibody, and the chemiluminescence was then measured.
All results were expressed as mean ± SEM. For all the measured variables, an analysis of variance was used to compare the changes among groups, and when significance was detected, a Student’s t-test with Bonferroni’s corrections was used to compare pairs of measured points. The patients’ demographic data and clinical outcome were analyzed among the groups by using Friedman’s significance test. Statistical significance was set at P < 0.05.
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Results
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There were no significant differences in demographic and operative characteristics among the groups (Table 1). As indicated in Table 2, eight patients had carotid stenosis (left, right or both carotid arteries impaired), and three patients had a history of stroke. As shown in Figure 1A, the patients in Group I (CABG with mild hypothermic CPB) or Group II (AAR with deep hypothermic CPB) exhibited a significant increase in serum NSE compared with the patients in Group III (CABG without CPB from 90 min after the initiation of CPB until the end of the operation). The NSE level was still increased in Group II 12 h after the end of surgery, but it had returned to normal in the patients in Group I. The S-100 concentration (Fig. 1B) was significantly larger in Groups I and II than in Group III from 90 min after the beginning of CPB until the end of CPB, and it had decreased to within the normal range (less than 0.5 µg/L) within 12 h of the end of the operation. In Group III, NSE and S-100 both stayed within the normal range throughout the study (Fig. 1, A and B). The jugular venous-arterial difference in lactate concentration is shown for each group in Figure 2. There were no differences among the groups throughout the operative period. At 90 min after starting CPB, SjO2 in Group II was higher (99.6% ± 0.2%) than in Group I (74.4% ± 3.6%) or Group III (66% ± 1.7%) (Fig. 3) because of the use of retrograde cerebral perfusion. At some measurement points, NIRS gave higher values in Group I and Group II than in Group III; however, there was no consistent pattern. Cerebral blood flow velocity measured by TCD was found to be variable (Fig. 4). in all three groups. In the EEG, two patients in Group I and one patient in Group II developed a seizure pattern at the end of the operation. All the other patients in the three groups showed a pattern (low amplitude and frequency) throughout the operation that was typical of patients under anesthesia.
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Figure 1. A, Dynamics of serum neuron-specific enolase (NSE). P < 0.05 versus Group III. B, Dynamics of serum S-100. P < 0.03 versus Group III. *P < 0.03 versus Group I. Data are mean ± SE 30 min cardiopulmonary bypass (CPB), 90 min CPB, 150 min CPB = time after beginning of CPB; after CPB = just after weaning from CPB; after 12 h = 12 h after end of operation. For Group III, all CPB points are at 60-min intervals (these patients underwent sham CPB).
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Figure 2. Dynamics of jugular-arterial lactate differences (delta lactate concentrations). Data are mean ± SE. Pre CPB = before starting CPB; 60 min CPB, 150 min CPB = time after beginning of CPB; after CPB = just after weaning from CPB. For Group III, all CPB points are at 60-min intervals (these patients underwent sham CPB).
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Figure 3. Dynamics of jugular vein oxygen saturation. P < 0.009 versus Group III. *P < 0.003 versus Group I. Data are mean ± SE. preCPB = before starting CPB; 30 min CPB, 60 min CPB, 90 min CPB, 120 min CPB, 150 min CPB = time after beginning of CPB; after CPB = just after weaning from CPB. For Group III, all "CPB" points are at 30-min intervals (these patients underwent sham CPB).
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Figure 4. Dynamics of blood velocity estimated by transcranial Doppler (TCD). Data are mean ± SE. Pre CPB = before starting CPB; 60 min CPB, 90 min CPB, 120 min CPB, 150 min CPB = time after beginning of CPB; after CPB = just after weaning from CPB. For Group III, all CPB points are at 30-min intervals (these patients underwent sham CPB).
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All the patients recovered after their operation. As shown in Table 2, four patients two from Group I [15.4%] and two from Group II [33.3%] sustained seizures either at the end of the operation or the day after the operation. Concomitant decreases in the values of NIRS and SjO2 were observed, but not in TCD. Bolus IV injections of thiamylal 100 mg and midazolam 5 mg were given, and continuous infusions of the same dosages of the drugs per hour were started. These patients required a more prolonged period of mechanical ventilation and hence regained consciousness later than the other patients (1–4 days) after the operation. For several days, they were confused, restless, or agitated and therefore spent more days in the intensive care unit. One had respiratory problems in the postoperative period, and a tracheostomy was performed on the 15th postoperative day. On the 3rd postoperative day, one patient in Group I (7.7%) and one patient in Group II (16.7%) showed evidence of a neurological deficit (Table 2). In contrast, no patients in Group III had postoperative neurological complications. However, statistically, there were no significant differences among the three groups in terms of postoperative neurological outcome.
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Discussion
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We found that the serum concentrations of NSE and S-100 were increases in patients undergoing CABG with mild hypothermic CPB and in patients undergoing AAR with deep hypothermic CPB. In contrast, patients undergoing CABG without CPB under normothermic conditions showed no increase in the concentration of either marker and no neurological complications. The increase of S-100 was more short-lived than that of NSE, and the S-100 level was highest in patients undergoing AAR with deep hypothermic CPB. It is therefore suggested that neuronal and astroglial cell injuries are both more likely to occur during cardiac surgery with mild or deep hypothermic CPB than when such surgery is performed without CPB under normothermia.
There is an increased incidence of neuropsychological impairment after cardiac surgery (indicating minor brain cell injury) (10,11). The markers NSE and S-100, which were introduced a few years ago, are thermostable, and their assay is not affected by heparin or protamine sulfate. We therefore used them to detect brain cell injury during different types of cardiac surgery.
NSE is a dimetric enzyme that catalyses the conversion of 2-phospho-d-glycerate to phosphoenolpyruvate in the glycolytic pathway, and it contains 
and 
subunits that are specific for neurons (12). In stroke, serum NSE concentrations may reflect the extent of brain damage, and they may be useful in the selection of patients with major stroke for more aggressive treatment during the acute phase (4). Schaarschmidt et al. (13) proposed the following ranges of serum NSE: 2–20 µg/L (normal), >30 µg/L (pathological), >115 µg/L (bad prognosis or lethal). In our study, the mean NSE level was larger than 30 µg/L in Group II patients (n = 6, with deep hypothermic CPB), and it remained more than 30 µg/L even 12 hours later. In Group I, the NSE was increased to 20–30 µg/L (which could be considered borderline levels). In contrast, the control group (Group III) showed no increases. Our data suggest that patients in Groups I and II may have had neuronal cellular injury, even though the injury may have been subclinical in some cases.
S-100 protein is an acidic calcium-binding protein found in the brain as homodimers of two isomeric subunits, and ß. S-100ß (ßß-S-100) is present in large concentrations in glial cells and Schwann cells, whereas S-100 (ß-S-100) is present in glial cells, but not in Schwann cells (14). S-100 protein is considered a marker of glial cell damage. Clinical data suggest that the normal level of serum S-100 is less than 0.2 µg/L (15). We set our normal range at less than 0.5 µg/L, the difference in normal values being explained by differences in the assay protocols. In our study, the greatest increase in serum S-100 protein was seen in patients undergoing AAR on weaning from deep hyperthermic CPB, and the level had returned to normal within 12 hours of the end of the operation (Fig. 1B). In patients of Group I (CABG with mild hypothermic CPB), the increase in S-100 was moderate. The time course of the present changes in S-100 is consistent with that in a previous report (15), and we confirmed that S-100 protein is a short-term biochemical marker by comparison with NSE (Fig. 1A). Indeed, the optimal sampling points are not later than 2–3 hours after potential cerebral damage. These NSE increases during cardiac surgery are consistent with the observations of Johnsson et al. (7). Our data suggest that astroglial injuries are more likely in patients under mild or deep hypothermic CPB than in patients without CPB under normothermic conditions.
However, several factors should be considered when interpreting data such as ours. First, it is well known that NSE is affected by hemolysis because it is contained within red cells and platelets. To avoid this hemolytic effect, we excluded patients with severe hemolysis. However, we cannot eliminate the possibility that subclinical hemolysis explains the differences. Second, hypothermia itself enhances the washout of these enzymes from the brain (16). We consider that the levels of NSE and S-100 seen in Group II are too high to be leakage from the brain at normal turnover rates. However, it is equally likely that these results may reflect changes in the kinetics of these enzymes as a result of changes in blood-brain barrier permeability during CPB. Third, two patients in Groups I and II suffered neurological complications. These patients had NSE and S-100 levels such as 25 and 23 µg/L, 5.09 and 1.7 µg/L, respectively. Only one of these results (5.09 µg/L) is outside of the two standard deviations of the entire values of Group I. Another two patients in Group II who developed seizures had levels of NSE and S-100 of 58 and 45 µg/L as well as 5.5 and 2.0 µg/L, respectively. These values are within the range of a standard deviation for the group values. Therefore, we failed to find any correlation between seizure episodes or neurological complications and the increases in NSE or S-100. It is possible that the small numbers of patients in our study precluded correlations. There may also be other explanations for this. In the central nervous system, different anatomical areas are responsible for different functions, and these differ widely in their structural characteristics. Hence, damage to the same number of neurons in the frontal lobe or temporal lobe (for example) will lead to different levels of neurological impairment. Nonetheless, our data suggest that the number of damaged brain cells was negligible in the patients not exposed to CPB because there were no increases in either NSE or S-100. This seems to be supported by the neurological outcome: no patient in this group sustained seizures or had neurologic complications in the perioperative period. In this sense, CABG without CPB under normothermia might be considered in patients with prexisting severe cerebrovascular disease. We performed brief neuropsychologic test that consisted of conversation and calculation and found no impairments in any patients. However, this test is not sufficient to detect subtle changes in neuropsychologic status, and therefore, other testing based on the more detailed interview (high cognitive function testing) should be performed in future studies.
We also simultaneously used the available intraoperative monitors/markers (NIRS, TCD, EEG, SjO2, Sj lactate) which are considered real-time instruments for detecting brain damage. Among these (Table 2), all patients with abnormal neurological examination on the third day and seizures in the intensive care unit were predicted by intraoperative EEG monitoring. It is therefore suggested that the EEG is a far more sensitive and specific measure for clinical and neurological dysfunction than NSE and S-100. NIRS and SjO2 are monitors used for evaluating the balance between cerebral blood flow and cerebral oxygen consumption, and both are useful during cardiac operations (17). Our NIRS values could have been affected by extracranial factors such as skin blood flow or hemoglobin levels, which vary with temperature and CPB, and the SjO2 is affected by the retrograde cerebral perfusion. In addition, although both NIRS and SjO2 can detect a global oxygen imbalance sufficient to lead to a severe neurological deficit, they cannot detect localized or mild ischemia such as might occur during CPB. Arterial-jugular vein lactate difference is another biochemical marker of cerebral ischemia that is used in cardiac operations (6). However, this marker is not sufficiently sensitive to detect a transient anaerobic state in brain cells (18) such as might have occurred in our study. TCD is a useful monitor of cerebral hypoperfusion in patients undergoing cardiac surgery (19). In our study, there were no significant differences in TCD data among the groups, and therefore, the presumed brain cell damage in our patients was probably not a result of changes in the velocity of blood flow in the middle cerebral artery.
In summary, during mild or deep hypothermic CPB, damage to both neuronal and glial cells likely occur. Further, our results suggest that patients undergoing CABG without CPB under normothermic conditions are less likely to suffer brain cell injury.
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Accepted for publication June 20, 2000.
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Abstract
Introduction
